Many inorganics are carcinogenic in exposed human populations while others are suspected of such activity. As carcinogens, inorganics are very hazardous because they are ubiquitous, non-biodegradable, bioaccumulated, and mimic essential elements in biological systems. Human exposure to inorganics is inevitable and defining their mechanisms of action is critical in assessing the nature and extent of the human health hazard posed by such exposure. Arsenic, cadmium and lead are distinct among metal carcinogens because they do not undergo spontaneous redox reactions and the creation of electrophilic species that directly attack DNA is unlikely. Thus, we are actively considering alternative, epigenetic mechanisms for these metals. Indirect mechanisms by which metals induce aberrant gene expression and malignant transformation under study include interactions with regulatory proteins, altered DNA methylation status, interactions with DNA binding proteins or alterations in receptor mediated processes. Basic aspects of site specific sensitivity are also being explored, and with cadmium poor responsiveness of the metallothionein (MT) gene often dictates susceptibility. Site specificity determinants for arsenic are as yet unknown but may be linked to the tissues that most actively methylate this metalloid. We find that during arsenic-induced malignant transformation, DNA becomes hypomethylated, which, in turn, facilitates aberrant oncogene activation, including activation of c-myc and c-met. This is likely due to the consumption of cellular methyl groups in arsenic metabolism which reduces their availability for DNA methyltransferases and consequently reduces activity. On the other hand, transformation by cadmium in vitro is associated with genomic DNA hypermethylation, which can be linked to tumor suppressor gene inactivation. We also find that cadmium can block apoptosis subsequent to DNA damage from direct acting genotoxins, which allows a greater portion of genetically damaged cells to escape normal cell check points and could be an important factor in an epigenetic mechanism of carcinogenesis. Cadmium is also associated with activation of proto- oncogenes in human prostate epithelial cells. Cadmium can also be anti- apoptotic in these cells as well. In addition, recent work from our Section in whole animals indicates that cadmium can induce prostate tumors in the dorsolateral lobe of the rat, a lobe considered analogous to the human organ. Prostate cancer is an important and often deadly human malignancy that has been linked with human exposure to cadmium. - Animal models, Chemical carcinogenesis, Proto-oncogenes, Transformation, Metalloprotein, Apoptosis,